Diagnostic Profiles

Insufficient Evidence for Using ANA, CCP, and RF in Evaluation of Musculoskeletal Pain in Children

A comparative effectiveness review by the Agency for Healthcare Research and Quality (AHRQ) found insufficient evidence to support the use of antinuclear antibody (ANA) and cyclic-citrullinated peptide (CCP) tests to diagnose either juvenile idiopathic arthritis (JIA) or pediatric systemic lupus erythematosus (SLE) in children younger than age 18 experiencing musculoskeletal pain. The review found low-strength evidence for using rheumatoid factor (RF) tests to diagnose JIA in children with undiagnosed musculoskeletal pain. However, since the available evidence on the latter shows a sensitivity of just 4.8%, the review indicated that clinicians should not rely on serologic tests alone to diagnose JIA.

AHRQ researchers conducted a systematic review encompassing 28 clinical studies published over a 50-year period and also characterized the prevalence and etiology of musculoskeletal pain in children. They found that the prevalence of musculoskeletal pain ranged from 2% in children age 12 to 52% in those age 18. Up to 30% have chronic pain lasting >6 months. Available evidence suggests that 97% of musculoskeletal pain is noninflammatory in origin.

The investigators found the reported prevalence of positive test results in healthy children to be 0-18% in the case of ANA, about 3% in the case of RF, and between 0.0-0.6% for CCP.

The researchers emphasized that none of the published literature involving these tests looked at clinically important outcomes, such as the impact of the test results on referrals, ordering additional tests, patient management, or patient and parent anxiety levels. In addition, none of the studies addressed the patient or clinical characteristics that could modify accuracy of the tests, such as age, sex, race, and history of recent infections.

Bioscore of Three Analytes Improves Identification of Sepsis in Intensive Care Patients

A bioscore combining values of three biomarkers in two cohorts of consecutively selected intensive care patients was significantly better at differentiating between patients with and without sepsis than any one of the markers considered individually (Am J Respir Crit Care Med 2012;186:65–71). Although each of the three analytes—soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), procalcitonin (PCT), and high-affinity immunoglobulin-Fc fragment receptor I CD64 on polymorphonuclear cells (PMN CD64 Index)—independently predicted infection, PMN CD64 Index yielded the best area under the receiver-operating characteristic curve (AUROC) at 0.95, compared with 0.91 for PCT and 0.73 for sTREM-1.

PCT has long been considered important in the early identification of sepsis, and several studies also have suggested that sTREM-1 and PMN CD64 Index might serve the same purpose. To evaluate the utility of the biomarkers in this regard, the authors measured them in 300 prospectively enrolled intensive care patients, with no exclusion criteria, and validated them in a separate population of 79 prospectively enrolled patients from a different intensive care unit.

In the inception cohort, 51% of patients were diagnosed with sepsis, and upon admission, all three biomarkers were higher in patients with sepsis compared with all others (P <0.002). In patients with sepsis, PCT and sTREM-1 concentrations were higher in those infected with gram-negative rather than gram-positive infections.

The authors developed the bioscore using thresholds determined through the AUROC analysis, and used it in a multiple logistic regression model. The diagnostic accuracy of the individual biomarkers and the bioscore were similar in both the inception and validation cohorts. AUROC in the validation cohort ranged from 0.73 for sTREM-1 to 0.95 for the bioscore, with P values for all <0.0001.

Other studies have compared the performance of eGFRcyst and eGFRcreat, but not in diabetics, who have a high risk of ESRD and death unrelated to ESRD. The authors used data from three long-term follow-up studies of the risk of ESRD to compare the two equations, including one cohort of 364 type 1 diabetics, another of 402 type 2 diabetics, and a third of 399 type 1 diabetics. Only patients with chronic kidney disease were included in each cohort. Patients in both the type 1 diabetes cohorts were similar, but the type 2 diabetics were on average 15–17 years older at enrollment and had higher mean eGFR, and a lower incidence of ESRD.

The researchers found CKD staging by eGFRcyst and eGFRcreat corresponded in 62–73% of type 1 diabetics. However, in comparison to this group, subjects with higher stages by eGFRcyst than eGFRcreat had a significantly higher risk of ESRD. Similarly, in comparison to those with concordant CKD staging by both methods, those with a lower CKD stage by eGFRcyst than by eGFRcreat had a lower risk of ESRD.

Normal Liver Enzymes Common in HFE C282Y Homozygotes with Hyperferritinemia

New research indicates that patients with hyperferritinemia who are HFE C282Y homozygotes have lower liver transaminase levels than nonhomozygotes (Hepatology 2012; 55:1722–26). This finding counters the common notion that patients with hemochromatosis have elevated serum transaminases, which is common in many liver diseases. The authors suggested that all Caucasian patients with hyperferritinemia should be evaluated for HFE hemochromatosis, regardless of their levels of serum transaminases.

The data is from a sub-study of the Hemochromatosis and Iron Overload Screening Study, which involved nearly 100,000 primary care patients who were screened for iron overload using ferritin, transferrin saturation, and HFE genotyping. In the sub-study, the investigators compared liver transaminase levels of 162 C282Y homozygotes and 1,367 C282Y nonhomozygotes. All patients had elevated levels of both ferritin—defined as >300 µg/L in men and >200µg/L in women—and transferrin saturation, defined as >50% in men and >45% in women.

In both men and women who were C282Y homozygotes, both the mean alanine aminotransaminase (ALT) and aspartate aminotransaminase levels were lower than in nonhomozygotes. Most C282Y homozygotes had ALT levels <40 IU/L. In contrast, patients with both elevated serum transaminase levels and elevated serum ferritin levels were less likely to be C282Y homozygotes.